Hepatitis E, caused by infection with waterborne hepatitis E virus (HEV) is endemic in several developing countries, particularly in Asia and Africa. In the Indian subcontinent, hepatitis E occurs as large outbreaks. Whereas the disease is usually self-limiting, about 1% of patients develop fulminant hepatic failure (FHF), a syndrome with 50-80% mortality. The disease is especially severe among pregnant women, who develop FHF more often and have mortality rates as high as 20-30% following infection with HEV. A prophylactic vaccine is being developed against this infection, no specific therapy is however yet available. To develop the latter, a better understanding of the mechanism of liver injury in HEV infection, whether the virus itself or the host's immune response, is needed. The lack of an in vitro culture system and a small animal model makes it difficult to determine whether the virus is cytopathic. The limited cellular immune response data currently available are based on studies of peripheral blood mononuclear cells and may not accurately reflect the immune events in the liver, the major site of injury. Also, no prognostic marker has yet been developed to help identify those patients with hepatitis E who are at risk for developing FHF. Our hypothesis is that the liver injury and severity of disease in hepatitis E are determined primarily by the host response to viral infection. This proposal, therefore, aims to (a) characterize the immune events in the liver tissue of patients with acute hepatitis E (number of CD4+ T cells, CD8+ T cells and NK cell, and their localization in relation to HEV antigen - using immunofluorescence and confocal microscopy), (b) characterize the expression of host genes in the liver, the primary target organ for infection (using microarray techniques), and (c) discovery of protein biomarkers in the plasma or urine for differentiation between acute self-limited and fulminant hepatitis E (using proteomic techniques), and validation in a separate group of patients. The information obtained from the proposed work will help advance our understanding of the mechanisms of liver injury in hepatitis E, will provide useful biomarkers to guide the clinical care of patients with this disease and may help identify potential targets for therapeutic intervention in patients with severe forms of this disease.